Melanin-concentrating hormone (MCH), a cyclic neuropeptide, consist of 19 amino acids, which was originally described in salmon pituitary and isolated from its extract (Kawauchi et al., Nature 305: 321-323 (1983)). Later MCH was identified in mammals also as a cyclic nonadeca peptide.
The first MCH receptor (which was called later MCHR1), a G-protein coupled receptor (GPCR), was identified with “reverse pharmacological” approach, namely it was shown, that in mammals MCH is the natural ligand of orphan GPCR (SLC1). Thereafter a second MCH receptor (MCHR2) was also identified. In human both receptor sub-type can be found, while in rodents only MCHR1.
The melanin-concentrating hormone receptor 1 (MCHR1) plays an important role in the regulation of the energy homeostasis, food intake, reward as well as the nutrition behaviour. The role of MCH in the energy homeostasis and food intake of mammals has long been studied (Qu et al., Nature 380: 243-247 (1996); Rossi et al., Endocrinology 138: 351-355 (1997); Shimada et al., Nature 396: 670-674 (1998)).
The neurons, producing the melanin-concentrating hormone (MCH), can be found in the tuberal region of hypotalamus, which is the integrating center of the neurohumoral regulation of the energy homeostasis and stress reactions. MCHR1 can be found in many regions of the brain and is distributed mainly in areas implicated in the regulation of nutrition, energy balance, emotion and stress. (Hervieu et al., Eur J Neurosci 12: 1194-16 (2000), Saito et al., J Comp Neurol 435: 36-40 (2001), Borowsky et al., Nat Med 8: 825-30 (2002)). The MCH is expressed mainly in the lateral hypothalamic area as well as in the subthalamic zona incerta.
In rodents the MCH simultaneously stimulates food intake as well as energy balance. (Pissios and Maratos-Flier, Trends Endocrinol Metabol 14: 243-48 (2003); Pissios et al., Peptides 30: 2040-44 (2009)). MCH expression is increased in fasted animals and in leptin-deficient ob/ob mice. Upon acute icy administration of MCH food intake substantially increased and catabolic activity decreased. (Qu et al., Nature 380: 243-47 (1996)). Cronic icy administration of MCH results in an encreased calorie uptake and a significant increase in bodyweight. Furthermore the treated animals showed—similarly to the human metabolic symptoms—an increased glucose, insulin and leptin level (Gomori et al., Am J Physiol Endocrinol Metab 284: E583-88 (2003)).
In line with this elimination of the MCH gen (KO) makes the mice resistant to diet-induced obesity (DIO=diet-induced obesity). Transgenic mice overexpressing the MCH gen consumed 10% more calories and gained 12% more weight than controls on high fat diet. High blood glucose and insulin-resistance also appeared, consistent with a prediabetic state (Ludwig et al., J. Clin. Invest. 107, 379-386 (2001)). The MCHR1 KO mice, exhibited slightly increased food intake, but are resistant to diet-induced obesity and their metabolism is increased (Shimada et al.: Nature 396: 670-674 (1998)).
Rodents treated with MCHR1 antagonist showed a decreased food intake and better metabolic condition, especially when they were placed on a high-fat diet (Pissios et al., Peptides 30: 2040-44 (2009); Ito et al., Eur J Pharmacol 624: 77-83 (2009)).
MCHR1 antagonists may play a role not only in the regulation of body weight, but also in the treatment of anxiety and depression (Smith et al., Neuropsychopharmacol 31: 1135-45 (2006); David et al., J Pharmacol Exp Ther 321: 237-48 (2007); Gehlert et al., J Pharmacol Exp Ther 329:429-38 (2009)).
The MCHR1 is also involved in the patogenesis of the experimentalcolitis which is considered to be the relevant modell of the human inflammatory bowel disease (e.g. Crohn disease). The systemic application of MCHR1 antibody or MCHR1 antagonist to rodents decreased the severity of the experimentally induced acut inflammation of the colon and increased the rate of recovery (Kokkotou et al., Proc Natl Acad Sci USA 105: 10613-18 (2008); Fitzpatrik et al., AGA Abstracts, Gastroenterology 136 (5 supl 1)A-403 (2009); Ziogas et al., Am J Physiol Gastrointest Liver Physiol 304: G876-84 (2013)).
The MCHR1 plays also a role in the development of acut intestinal inflammation which was proved in mice treated with C. difficile A toxin (Kokkotou et al., Gut 58: 34-40 (2009)).
Antagonization of MCHR1 with low molecular weight substances is considered to be a promising strategy for the treatment of obesity, depression, anxiety and inflammatory bowel diseases. The following patent applications deal with MCH receptor antagonists: Tempest et al. WO2005/019240, Washburn et al. WO2008/134480; Suh et al. WO2008/140239; Stein et al. WO2009/009501; Johansson et al. WO2010/125390; Christensen et al. WO2010/141539; Lin et al. WO2011/127643; Oost et al. WO2013/131935; Qin et al. WO2013/149362; Ahmad et al. WO2014/039411.
Since the discovery of the MCH receptors a large number of compounds with antagonistic activity were described. Despite several clinical investigations none of the compounds reached the therapeutic application, even Phase 1 clinical studies were carried out only with 6 compounds. The first investigations were carried out in 2004 by the Glaxo Group and Amgen with the compounds called GW856464 and AMG-076/071, respectively, with obesity indication. According to the Phase 1b “proof of confidence” investigation of Bristol-Meyers Squibb (2011) the compound BMS-830216 proved to be inactive. The last Phase 1 investigation was launched by Astra-Zeneca in March 2014 and was terminated in October. In most cases the poor pharmatokinetic profile and the CYP induction were responsible for the failor of these compounds.
There is a need for developing such melanin-koncentrating hormon antagonists, which would be suitable for the treatment and/or prevention of obesity, obesity related comorbid conditions and complications, diabetes, metabolic disorders, psychiatric diseases accompanied by weight gain, inflammatory bowel diseases, affective dysfunctions, anxiety disorders, sleep-wake cycle disorders, substance abuse and addictive disorders.